Overcoming T Cell Tolerance Against Endogenous Choroid Plexus Tumors Using a Combination Immunotherapy
Gawlick, Ute
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Permalink
https://hdl.handle.net/2142/82501
Description
Title
Overcoming T Cell Tolerance Against Endogenous Choroid Plexus Tumors Using a Combination Immunotherapy
Author(s)
Gawlick, Ute
Issue Date
2005
Doctoral Committee Chair(s)
Roy, Edward J.
Department of Study
Neuroscience
Discipline
Neuroscience
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Neuroscience
Language
eng
Abstract
We target T cells escaping clonal deletion to study effects of a combination of immunotherapies against endogenously arising choroid plexus tumors. The model we use is the SV11 mouse transgenic for large T antigen of simian virus 40. Mice are immunologically tolerant to the choroid plexus tumor. We found that systemic administration of the proinflammatory TH1 cytokine, IL-12, increased survival and tumor T cell infiltrate. The addition of costimulation through an anti-CD28/Folate bispecific conjugate, PV-1 Fab/Folate, further enhanced survival and dramatically slowed tumor growth. Furthermore, proliferating CD8 T cells were found in tumors of treated animals. However, upon treatment withdrawal, tumors rapidly progressed and all animals eventually succumbed to the tumor. To supplement T cell activation, we investigated the possible recruitment of microglia, hoping to increase endogenous antigen presentation. Microglia phagocytosed apoptotic tumor cells and present class I MHC peptide antigen, inducing proliferation of naive CTLs in vitro. Furthermore, microglia enhanced proliferation of naive peptide specific CTLs incubated with primary splenocytes and high affinity peptide. We postulate that supplementing the immune response created with IL-12 and PV-1 Fab/Folate by increasing antigen presentation, peripherally activated T cells infiltrating the tumor parenchyma will receive the required stimulation for efficient activation. Immunotherapy with naive low-affinity, anti-tumor CTLs will most likely involve combinations of strategies stimulating the signaling pathways needed to activate and sustain a specific T cell response strong enough to overcome tumor growth, CNS immunosuppression, and self-tolerance.
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